rs3730966

chr19-48137671-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000234.3(LIG1):c.1105G>A(p.Val369Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,604,372 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0020 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (9 hom.)
• Consequence: LIG1 NM_000234.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.637

Genes affected

LIG1 (HGNC:6598): (DNA ligase 1) This gene encodes a member of the ATP-dependent DNA ligase protein family. The encoded protein functions in DNA replication, recombination, and the base excision repair process. Mutations in this gene that lead to DNA ligase I deficiency result in immunodeficiency and increased sensitivity to DNA-damaging agents. Disruption of this gene may also be associated with a variety of cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003688544).
• BP6: Variant 19-48137671-C-T is Benign according to our data. Variant chr19-48137671-C-T is described in ClinVar as [Benign]. Clinvar id is 1166253.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00196 (299/152308) while in subpopulation AMR AF= 0.0174 (267/15304). AF 95% confidence interval is 0.0157. There are 6 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG1	NM_000234.3	c.1105G>A	p.Val369Ile	missense_variant	13/28	ENST00000263274.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG1	ENST00000263274.12	c.1105G>A	p.Val369Ile	missense_variant	13/28	1	NM_000234.3	P4

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152190 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00265 AC: 634 AN: 239330 Hom.: 6 AF XY: 0.00196 AC XY: 256 AN XY: 130884

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.000580 AC: 842 AN: 1452064 Hom.: 9 Cov.: 32 AF XY: 0.000476 AC XY: 344 AN XY: 722626

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152308 Hom.: 6 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74470

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000524 Hom.: 3

Bravo AF: 0.00268

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00162 AC: 197

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.18
Dann	Benign	0.40
DEOGEN2	Benign	0.062	T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.77	T;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.65	N;.;.;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.56	N;N;N;.
REVEL	Benign	0.016
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;B;.;.
Vest4		0.083
MVP		0.048
MPC		0.22
ClinPred		0.00058	T
GERP RS		0.15
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.027
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3730966; hg19: chr19-48640928; COSMIC: COSV99619015; COSMIC: COSV99619015;